Resveratrol

Resveratrol is a naturally occurring polyphenolic compound that has garnered significant attention in the scientific community for its potential role in promoting human longevity and healthspan. This compound is found in various plants, where it acts as a line of defense against stressors such as infection or ultraviolet radiation.

Resveratrol is a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens such as bacteria or fungi. Its molecular formula is C₁₄H₁₂O₃, and it belongs to a class of compounds known as stilbenes.

The potential of resveratrol to impact longevity stems from its ability to modulate several biological pathways that are implicated in the aging process. It is renowned for its antioxidant and anti-inflammatory properties, which can mitigate the damaging effects of oxidative stress and inflammation, two key contributors to aging and age-related diseases. Additionally, resveratrol is known to activate sirtuins, a family of proteins that play a crucial role in cellular health and longevity.

Historical Context

Discovery of Resveratrol

Resveratrol was first identified in 1939 by Michio Takaoka from the roots of the white hellebore (Veratrum grandiflorum). However, it gained significant attention in the 1990s when its presence was discovered in red wine, suggesting a possible explanation for the French Paradox – the observation that French people have a relatively low incidence of coronary heart disease, despite having a diet rich in saturated fats.

Initial Studies and Findings

The early studies primarily focused on the antioxidant properties of resveratrol. Researchers found that it had the ability to scavenge free radicals and reduce oxidative stress, which are key contributors to aging and age-related diseases. These initial findings sparked interest in resveratrol as a potential anti-aging compound.

Evolution of Resveratrol Research

Over the years, research on resveratrol has expanded to explore its impact on a variety of biological processes related to aging. Studies have investigated its role in inflammation reduction, sirtuin activation, and its potential to mimic the effects of caloric restriction – one of the few scientifically supported interventions known to extend lifespan in various organisms. The body of research has grown to include clinical trials aiming to understand the effects of resveratrol on human health and longevity.

Natural Sources

Resveratrol is primarily found in the skin of grapes and in red wine, but it is also present in other fruits, vegetables, and plants. Here are some of the natural sources of resveratrol:

Grapes and Wine

• Red Grapes: The skin of red grapes is one of the richest sources of resveratrol.
• Red Wine: Produced from red grapes, red wine is a popular source of resveratrol, with levels varying depending on the type of wine and where the grapes are grown.

Berries

• Blueberries: Contain moderate amounts of resveratrol.
• Cranberries: Another berry that is a source of resveratrol.
• Mulberries: These berries are also known to contain resveratrol.

Peanuts

• Raw Peanuts: Peanuts, especially the skins, contain resveratrol.
• Peanut Butter: A source of resveratrol, though levels are lower compared to raw peanuts.

Biological Mechanisms

Resveratrol is renowned for its diverse biological mechanisms that may contribute to its potential longevity-enhancing properties. This section explores the intricate biological pathways and processes influenced by resveratrol.

Antioxidant Properties

Resveratrol exhibits powerful antioxidant properties, which play a crucial role in combating oxidative stress, a key contributor to aging and age-related diseases. It neutralizes free radicals and reduces oxidative damage to cells, potentially prolonging cellular health and vitality.

Anti-Inflammatory Effects

The anti-inflammatory effects of resveratrol are significant in the context of aging. Chronic inflammation is implicated in numerous age-related conditions, and resveratrol’s ability to modulate inflammatory responses could be pivotal in mitigating the impacts of such conditions.

Sirtuin Activation and Regulation

Resveratrol is known to activate sirtuins, a family of proteins associated with aging and longevity. Sirtuins regulate various cellular processes, including DNA repair, metabolism, and stress resistance, and are believed to extend lifespan by promoting cellular stability and survival.

Impact on Telomeres

Telomeres are the protective caps at the ends of chromosomes that shorten as cells divide. Resveratrol is suggested to influence telomere length and function, potentially delaying cellular senescence and extending the lifespan of cells.

Additional Mechanisms

In addition to the mechanisms listed above, resveratrol has also been shown to:

• Activate AMPK, a protein kinase that plays a central role in regulating cellular metabolism and energy homeostasis. AMPK activation is associated with a variety of health benefits, including reduced inflammation, improved insulin sensitivity, and increased stress resistance.
• Induce autophagy, a cellular process that removes damaged or dysfunctional components. Autophagy is essential for maintaining cellular health and function, and it is thought to play a role in preventing age-related diseases.
• Modulate the expression of a variety of genes, including genes involved in cell survival, apoptosis, and senescence. By altering gene expression, resveratrol can influence the aging process at a fundamental level.

Overall, the research on the biological mechanisms of resveratrol is still in its early stages, but it is clear that this compound has a wide range of effects on cellular processes that are relevant to aging. Further research is needed to fully understand how resveratrol can be leveraged to promote longevity and improve healthspan.

Resveratrol and Aging

Resveratrol has garnered significant attention in the scientific community for its potential role in promoting health and longevity. This section delves into the intricate relationship between resveratrol and aging, exploring its effects on lifespan and age-related diseases.

Effects on Lifespan

Resveratrol is believed to extend lifespan through its interaction with certain proteins and genes associated with aging. Studies in various organisms, including yeast, worms, flies, and mice, have shown promising results, indicating an increase in lifespan with resveratrol supplementation.

Impact on Age-Related Diseases

Resveratrol’s potential in mitigating the risk of several age-related diseases is under extensive research. It has shown promise in the prevention and management of diseases such as:

• Cardiovascular Diseases: Resveratrol helps in improving heart health by reducing inflammation and oxidative stress.
• Neurodegenerative Diseases: It has potential neuroprotective effects, which can be beneficial in conditions like Alzheimer’s and Parkinson’s disease.
• Cancer: Resveratrol may inhibit the growth of cancer cells and induce apoptosis, showing potential as an anti-cancer agent.

Cellular Senescence and Apoptosis

Resveratrol is studied for its role in reducing cellular senescence and promoting apoptosis, which are crucial processes related to aging and disease. It modulates various signaling pathways, influencing cell cycle, inflammation, and survival.

Caloric Restriction Mimetic

One of the mechanisms by which resveratrol is thought to impact aging is by mimicking the effects of caloric restriction, a well-known intervention for extending lifespan. It activates sirtuins (in particularly SIRT1), proteins associated with longevity, and influences metabolic processes related to aging.

A recent study in a randomized trial involving adults aged 55 to 65 compared the effects of resveratrol supplementation to a caloric-restricted diet. Both interventions raised circulating SIRT1 levels and reduced plasma noradrenaline, suggesting cardiovascular benefits. However, the study found differences between the groups in vascular reactions. Specifically, improvements in nitrate-mediated vasodilation (NMD) were seen only with caloric restriction, not with resveratrol. Additionally, SIRT1 was linked to enhanced flow-mediated vasodilation (FMD) in men but not in women. This suggests that while resveratrol mirrors some benefits of caloric restriction, it doesn't capture all, especially regarding vascular effects.

Forms of Resveratrol

Resveratrol exists in two geometric isomers: cis-resveratrol and trans-resveratrol.

• Trans-resveratrol is the most abundant and biologically active form of resveratrol in plants. It is the form that has been most studied in scientific research and is thought to be responsible for the majority of the health benefits associated with resveratrol.

• Cis-resveratrol is less abundant in nature and less biologically active than trans-resveratrol. However, it has still been shown to have some health benefits, such as antioxidant and anti-inflammatory effects.

In addition to cis- and trans-resveratrol, there are also a number of other forms of resveratrol, including:

• Piceatannol: Piceatannol is a metabolite of resveratrol that is found in red grape skins and Japanese knotweed. It has been shown to have some similar health benefits to trans-resveratrol, such as antioxidant and anti-cancer effects.
• Resveratrol glucosides: Resveratrol glucosides are conjugated forms of resveratrol that are linked to glucose molecules. These forms of resveratrol are less bioavailable than trans-resveratrol, but they may be more stable and easier to store.
• Resveratrol dimers and oligomers: Resveratrol dimers and oligomers are formed when two or more molecules of resveratrol link together. These forms of resveratrol have been shown to have some unique biological activities, such as anti-cancer and anti-inflammatory effects.

The most common form of resveratrol available as a supplement is trans-resveratrol. Trans-resveratrol supplements are typically made from grape seed extract or Japanese knotweed extract.

Formulations and Bioavailability

Trans-Resveratrol

Trans-resveratrol unfortunately suffers from poor bioavailability and water solubility. Its solubility in water is less than 0.05 mg/ml. Studies have indicated varying plasma concentrations after repeated doses of resveratrol:

Reported resveratrol plasma concentration in humans after repeated doses of resveratrol (studies after 2010).

Number of Participants, Characteristics, Study Type	Dose (mg/day)	Days	Administration	Peak Plasma Concentration (ng/mL)
6, low BMI	2125	11	Tablet and drink	903.0
6, high BMI				245.0
35, healthy males, cross-over study	800	5	Capsule	0.56
			Dairy drink	0.61
			Soy drink	0.58
			Protein-free drink	0.70
7, healthy	500	28	Capsule with Piperine	2967.25
40, healthy, repeated sequential dosing	500	29	Caplet	43.8
	1000			141
	2500			331
	5000			967
6, patients with hepatic metastases, randomized double-blind clinical trial	5000	14	Micronized resveratrol mixed in liquid	1942
8, healthy subjects	2000	7	Capsule	1274
19, overweight or obese, randomized, double-blind, placebo-controlled, crossover intervention	30	6	Capsule	181.31
	90			532.00
	270			1232.16

After consumption, 77-80% of resveratrol gets absorbed into the bloodstream through active transport via the intestinal epithelial cells. Once in the bloodstream, it associates with albumin and lipoproteins. Despite its efficient absorption, resveratrol possesses a short half-life of around 1.5 hours. This is attributed to its rapid absorption in the intestine and subsequent degradation in the liver. A significant amount of ingested resveratrol, approximately 49–61%, is eventually excreted through urine.

Several factors lead to differences in how individuals respond to resveratrol intake:

• Gut Microbiota Composition: The unique blend of microorganisms in one's gut.
• Genetic Differences: Variations in genes that affect metabolism enzymes (like UGTs and SULTs) and transporters.
• Ethnicity & Geography: People from different ethnic backgrounds or geographical locations may metabolize resveratrol differently.
• Lifestyle & Diet: Personal habits and food choices can influence resveratrol processing.
• Natural Variation: Humans naturally vary, leading to different responses to resveratrol .

Resveratrol with Piperine

In 2021 Randomized Controlled Trial, participants receive a single dose of resveratrol 2500 mg, with piperine in 0 mg, 5 mg or 25 mg dose. Despite the observation of piperine coadministration significantly increasing bioavailability (C_max and AUC) of resveratrol in C57BL mice, no significant increase in resveratrol or decrease in resveratrol glucuronide could be observed in healthy adults taking 2500 gm of resveratrol with piperine (5 or 25 mg) as compared to resveratrol alone.

Micronized Resveratrol

Micronized resveratrol is a form of resveratrol that has been ground into very small particles. This makes it easier for the body to absorb and use the resveratrol.

There is some evidence to suggest that micronized resveratrol may have higher bioavailability than other forms of resveratrol. For example, one study found that micronized resveratrol was absorbed twice as well as standard resveratrol powder.

However, more research is needed to confirm the bioavailability of micronized resveratrol and to determine whether it is more effective than other forms of resveratrol.

Liposomal Resveratrol

There are a number of liposomal resveratrol supplements on the market that claim to have higher bioavailability than other forms of resveratrol. However, there is no clinical trial evidence to support this claim.

Dosage and Administration

Recommended Dosage

The recommended dosage for adults is generally between 150 to 500 mg per day, although this can vary based on individual health conditions and specific product formulations. In a study , participants received resveratrol for 29 days at doses of 0.5g, 1.0g, 2.5g, or 5.0g.

Dr. David Sinclair takes 500 mg resveratrol in the morning.

Forms of Administration

• Oral Supplements: Resveratrol is most commonly available in capsule or tablet form, taken orally with water.
• Liquid Form: Some people prefer liquid resveratrol, which can be mixed with water or another beverage.
• Topical Applications: Resveratrol is also found in some skincare products due to its antioxidant properties.

Safety

Resveratrol is generally considered safe when taken in recommended amounts, but excessive consumption can lead to side effects. In a study, it was found to be safe as no severe adverse reactions were observed based on clinical, biochemical, or hematological analyses.

Side Effects

Some people may experience gastrointestinal issues, headaches, or a feeling of jitteriness. In the mentioned study , the majority of adverse events in the higher doses (2.5g and 5.0g) were gastrointestinal symptoms, including nausea, flatulence, abdominal discomfort, and diarrhea. Symptoms typically began 2-4 days into the regimen and improved as the day progressed but would return after the next dose. They resolved within 2 days of completing the 29-day regimen.

Lifestyle and Synergistic Approaches

Combining Resveratrol with a Healthy Lifestyle

• Physical Activity: Regular exercise can enhance the benefits of resveratrol in promoting cardiovascular health and reducing the risk of chronic diseases.
• Balanced Diet: A diet rich in fruits, vegetables, lean proteins, and healthy fats can complement the effects of resveratrol.
• Adequate Sleep: Quality sleep is crucial for overall well-being and can maximize the potential benefits of resveratrol on longevity.
• Stress Management: Managing stress through relaxation techniques such as meditation and yoga can be beneficial in conjunction with resveratrol supplementation.

Synergistic Effects with Other Supplements

• Quercetin: When combined with resveratrol, quercetin can enhance anti-inflammatory and antioxidant effects.
• Pterostilbene: This compound is similar to resveratrol and can boost its effects on sirtuin activation and cellular health.
• Curcumin: The combination of resveratrol and curcumin can offer enhanced protection against inflammation and oxidative stress.

Dietary Considerations

• Caloric Restriction: A reduced calorie intake can potentiate the effects of resveratrol on lifespan extension.
• Polyphenol-Rich Foods: Consuming foods high in polyphenols, such as berries and dark chocolate, can complement the benefits of resveratrol.
• Alcohol Consumption: Moderate consumption of red wine, a source of resveratrol, can be part of a healthy lifestyle, but excessive alcohol intake can negate the benefits.